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Ischemic Heart Disease
-Angina Pectoris
The leading cause of mortality in the United States
More than 500,000 deaths per year
Coronary
artery
Enlarged view of
coronary artery
Plaque
Three types of angina
Stable angina/Classic angina/Effort angina
Variant angina/Prinzmetal angina
Unstable angina/Crescendo angina
Normal coronary artery
Atherosclerosis
Atherosclerosis
with blood clot
Coronary spasm
Normal
Stable angina
Unstable angina
Variant angina
— Imbalances in myocardial oxygen demand and supply
Coronary Flow Reduction Endothelial dysfunction
Causes
Stable angina Unstable angina Variant angina
Treatment strategy - correct the imbalance
Stable angina:
Decreasing cardiac work to reduce oxygen demand
Unstable angina:
Increasing oxygen delivery and decreasing oxygen
demand
Variant angina:
Spasm of coronary vessels reversed by nitrates,
calcium channel blockers
Determinants of oxygen demand
Wall stress
Intraventricular pressure
Ventricular radius (volume)
Wall thickness
Heart rate
Contractility
Arterial blood pressure
Drugs of modulating oxygen demand
Determinants of oxygen supply
Coronary blood flow
Metabolic products
Autonomic activity
Pharmacological agents
Coronary vascular
bed resistance
Aortic diastolic pressure
Duration of diastole
Vascular tone
Afterload: systolic ventricular wall stress
Preload: end-diastolic ventricular wall
stress
Right coronary artery
Left anterior descending coronary artery
Left circumflex coronary artery
Vascular tone of the coronary arteries
Perfusion of the heart
Myocardial O2
SUPPLY
Veins (capacitance vessels) Arterioles (resistance vessels)
Capillaries
Heart(pump)
Arteriolar toneVenous tone
Preload Afterload
Ventricular wall stress
Myocardial O2
DEMAND
Peripheral vascular
resistanceArterial blood pressure
Sites of drugs action-Nitrates,
Calcium channel blockers
NO
Reduce heart rate, contractility
Stabilize depolarization
Sites of drugs action - Sildenafil
Sildenafil/Viagra
Regulates blood
flow in the penis
Drugs used to treat angina
Nitrates
Calcium channel blockers
blockers Heart rate
Ventricular volume
Blood pressure
Contractility
Nitrates
Nitroglycerin (NTG)
(glyceryl trinitrate)
• Keep it in tightly closed glass container
• Volatilization and adsorption to plastic surfaces
• Not sensitive to light
Pharmacokinetics
Organic nitrate reductase
Oral bioavailability LOW
Sublingual
Transdermal
Buccal
Nitroglycerin
Isosorbide dinitrates
Mechanism of action - Nitrates
Nitrates
Glutathione S-transferase
Nitroglycerin
Experiment
Norepinephrine (NE)
Dilation of peripheral
capacitance veins Mildly dilate arteriolar
resistance vessels
Organ system effects of NTG
Side effects of NTG
• Orthostatic hypotension
• Syncope
• Artery pulsation and throbbing headache
• Negative inotropic effect
Pseudocyanosis
Fe3+
• Pseudocyanosis
• Tissue hypoxia
• Death
hemoglobin methemoglobin
Drugs for erectile dysfunction
Sildenafil (Viagra)
Tadalafil
Vardenafil
Corpora cavernosa
Preventing apoptosis
and cardiac remodeling
after ischemia and
reperfusion
Toxicity - Nitrates
Acute adverse effects
Orthostatic hypotension
Tachycardia
Throbbing headache
Tolerance
Sulfhydryl group
Reactive oxygen species (ROS)
Calcitonin gene-related peptide (CGRP)
( a potent vasodilator)
Carcinogenicity
Nitrosamines
Animal studies show a powerful carcinogens
Strong epidemiologic correlation between the
incidence of esophageal and gastric carcinoma
and the nitrates content of food
Beneficial and deleterious effects of nitrates
Effect Result
Potential beneficial effects
Decreased ventricular volume Decreased myocardial oxygen requirement
Decreased arterial pressure
Decreased ejection time
Vasodilation of epicardial coronary arteries Relief of coronary artery spasm
Increased collateral flow Improved perfusion to ischemic myocardium
Decreased left ventricular diastolic pressure Improved subendocardial perfusion
Potential deleterious effects
Reflex tachycardia Increased myocardial oxygen requirement
Reflex increase in contractility
Decreased diastolic perfusion time due to tachycardia Decreased coronary perfusion
Nitrate and nitrite drugs used in angina
Amyl nitrite Nitroglycerin
Isosorbide dinitrate
Drug Dose Duration of Action
Short-acting
Nitroglycerin, sublingual 0.15-1.2 mg 10-30 min
Isosorbide dinitrate, sublingual 2.5-5 mg 10-60 min
Amyl nitrite, inhalant 0.18-0.3 mL 3-5 min
Long-acting
Nitroglycerin, oral sustained-action 6.5-13 mg per 6-8 hours 6-8 hrs
Nitroglycerin, 2% ointment, transdermal 1-1.5 inches per 4 hours 3-6 hrs
Nitroglycerin, slow-release, buccal 1-2 mg per 4 hours 3-6 hrs
Nitroglycerin, slow-release patch, transdermal 10-25 mg per 24 hours 8-10 hrs
Isosorbide dinitrate, sublingual 2.5-10 mg per 2 hours 1.5-2 hrs
Isosorbide dinitrate, oral 10-60 mg per 2-4 hours 4-6 hrs
Isosorbide dinitrate, chewable oral 5-10 mg per 2-4 hours 2-3 hrs
Isosorbide mononitrate, oral 20 mg per 12 hours 6-10 hrs
Under investigation
Nicorandil
Reduces both
preload and afterload
Activation of cardiac KATP channels
Which of the following is a common direct effect of nitroglycerin?
A. Increased heart rate
B. Increased afterload
C. Increased venous capacitance
D. Increased preload
Calcium channel blocker Nitrates
Ca2+
Calcium channels
Type Channel Name Where Found Properties of the calcium
Current
Blocked by
L Cav1.1-Cav1.3 Cardiac, skeletal, smooth
muscle, neurons, endocrine
cells, bone
Long, large, high threshold Verapamil, DHPs, Cd2+, -aga-IIIA
T Cav3.1-Cav3.3
Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni2+, mibefradil
N Cav2.2
Neurons, sperm Short, high threshold Ziconotide, gabapentin, Cd2+
P/Q Cav2.1
Neurons Long, high threshold -CTX-MVIIC, -aga-IVA
R Cav2.3
Neurons, sperm Pacemaking SNX-482, -aga-IIIA
Chemistry – calcium channel blockers
High first-pass effect, high plasma binding, and extensive metabolism
Mechanism of action - calcium channel blockers
Nifedipine
Verapamil
Diltiazem
Smooth muscle
Vascular
Bronchiolar
Gastrointestinal
Uterine
• Peripheral vascular resistance-effort angina
• Coronary artery tone-variant angina
Dihydropyridines
Diltiazem
Verapamil
Cardiac muscle
Reduce SA and AV action potential
Reduce cardiac contractility
Reduce cardiac output
Nifedipine/dihydropyridines
Verapamil
Diltiazem
Skeletal muscle
CCBs do not affect
skeletal muscle
Cerebral vasospasm
Nimodipine Nicardipine
Prevent cerebral vasospasm
associated with stroke
Other aspects – Calcium channel blocker
Minimally affect glands and nerve due to calcium channel type
Verapamil inhibit insulin release
Interfere with platelet aggregation
Block P-glycoprotein
Reverse the resistance of cancer cells
Osteoporosis, fertility disorders, male contraception,
immune modulation, schistosomiasis
Toxicity – calcium channel blocker
Cardiac depression
Cardiac arrest
Bradycardia
Atrioventricular block
Heart failure
Immediate-acting Nifedipine increase the risk of MI
Flushing, dizziness, nausea, constipation, peripheral edema
Clinical effects – calcium channel blocker
Decrease myocardial contractile force
Decrease arterial and intraventricular pressure
Left ventricular wall stress declines
Decrease heart rate
Decrease myocardial
oxygen demand
Relieve and prevent the focal coronary artery spasm
-Variant angina
Most effective prophylactic treatment for variant angina
Target selectivity – calcium channel blocker
Verapamil
Diltiazem
Reflex tachycardia occurs with nifedipine
Tachycardia
Decreasing ventricular response in
atrial fibrillation of flutter
Clinical pharmacology of calcium channel-blocker
Drug Oral
Bioavailability (%)
Half-life
(hours)
Indication Dosage
Dihydropyridines
Amlodipine 65-90 30-50 Angina, hypertension
5-10 mg orally once daily
Felodipine 15-20 11-16 Hypertension 5-10 mg orally once daily
Isradipine 15-25 8 Hypertension 2.5-10 mg orally once daily
Nicardipine 35 2-4 Angina, hypertension 20-40 mg orally every 8 hours
Nifedipine 45-70 4 Angina, hypertension
3-10 mcg/kg IV; 20-40 orally every 8 hours
Nimodipine 13 1-2 Subarachnoid hemorrhage 40 mg orally every 4 hours
Nisoldipine <10 6-12 Hypertension 20-40 mg orally once daily
Nitrendipine 10-30 5-12 Investigational 20 mg orally once or twice daily
Miscellaneous
Diltiazem 40-65 3-4 Angina, hypertension 75-150 mcg/kg IV; 30-80 mg orally every 6
hours
Verapamil 20-35 6 Angina, hypertension,
arrhythmias, migraine
75-150 mcg/kg IV; 80-160 mg orally every
8 hours
Clinical considerations – calcium channel blocker
Low blood pressure
Verapamil/diltiazem are better than DHP
Atrial tachycardia, flutter, fibrillation
Verapamil/diltiazem are better due to the antiarrhymic effects
Unstable angina
Immediate-release short-acting CCBs increase the risk of adverse cardiac
events
Which muscle may not be affected by calcium channel blockers?
A. Cardiac muscle
B. Bronchiolar smooth muscle
C. Skeletal muscle
D. Gastrointestinal smooth muscle
blockers
Reduce oxygen demand by decreasing heart rate,
blood pressure and contractility
NE: norepinephrine
Gs: G-stimulatory protein
AC: adenylyl cyclase
PK-A: cAMP-dependent protein kinase
SR: sarcoplasmic reticulum
Clinical aspects - blocker
Silent/ambulatory ischemia
Myocardial infarction
Hypertension
Stable angina
Side effects - blocker
Increase in end-diastolic volume
Increase in ejection time
Myocardial oxygen
requirement
Propranolol Nitroglycerin
Asthma and other bronchospastic conditions
Severe bradycardia
Atrioventricular blockade
Bradycardia-tachycardia syndrome
Unstable left ventricular failure
Contraindications - blocker
Complications - blocker
Fatigue
Impaired exercise tolerance
Insomnia
Unpleasant dreams
Worsening of claudication
Erectile dysfunction
New drugs
Drugs under investigation for use in angina
Metabolic modulators, eg, trimetazidine, ranolazine
Direct bradycardic agents, eg, ivabradine
Potassium channel activators, eg, nicorandil
Rho-kinase inhibitors, eg, fasudil
Protein kinase G facilitators, eg, detanonoate
Sulfonylureas, eg, glybenclamide
Thiazolidinediones
Vasopeptidase inhibitors
Nitric oxide donors, eg, L-arginine
Capsaicin
Amiloride
Ranolazine was patented in 1986, and then approved for use in the US
in 2006 for angina patients who remain symptomatic despite being on
one or more of the standard treatments
Ranolazine acts by shifting ATP production away from fatty acid oxidation
in favor of glucose oxidation
Ranolazine
Ranolazine
Sodium channel blockers
Ivabradine
Efficacy similar to that of calcium channel blockers and
Beta blockers, but lack of effect on gastrointestinal and
bronchial smooth muscle
Inhibit the
hyperpolarization-
activated sodium
channel in the
sinoatrial node
Clinical pharmacology
Atherosclerotic disease of the coronaries (CAD)
Smoking, hypertension, hyperlipidemia, obesity
Antiplatelet agents/Aspirin, clopidogrel
Lipid-lowering agents/statins
Aspirin
Clopidogrel Statins
Effort angina Nitrates Alone -Blockers or Calcium Channel
Blockers
Combined Nitrates with blockers or
Calcium Channel Blockers
Heart rate Reflex increase Decrease Decrease
Arterial pressure Decrease Decrease Decrease
End-diastolic
volume
Decrease Increase None or decrease
Contractility Reflex increase Decrease None
Ejection time Decrease Increase None
Variant angina
Nitrates
Calcium channel blockers
No surgical revascularization and angioplasty
Normal coronary artery
Atherosclerosis
Atherosclerosis
with blood clot
Coronary spasm
Variant angina
Unstable angina
Aspirin
Clopidogrel
Unstable angina
Peripheral artery disease
Pentoxifylline
Cilostazol
Physical therapy and exercise training
is of proven benefit.
Summary Subclass Mechanism of action Effects Clinical
applications
Pharmacokinetics,
toxicities, interactions
NITRATES
Nitroglycerin
Releases NO in smooth muscle Smooth muscle relaxation,
especially in vessels
Angina: Sublingual form for
acute episodes oral and
transdermal form for
prophylaxis IV form for acute
coronary syndrome
Very high first-pass effect, so
sublingual dose is much smaller than
oral high lipid solubility ensures
rapid absorption Toxicity:
Orthostatic hypotension, tachycardia,
headache Interactions: Synergistic
hypotension with phosphodieasterase
type 5 inhibitors (sildenafil)
BETA BLCKERS
Propranolol
Nonselective competitive
antagonist at adrenoceptors
Decreased heart rate, cardiac output,
and blood pressure decrease
myocardial oxygen demand
Prophylaxis of angina Oral and parenteral, 4-6 h duration of
action Toxicity: Asthma,
atrioventricular block, acute heart
failure, sedation Interactions:
Additive with all cardiac depressants
CALCIUM CHANNEL
BLOCKERS
Verapamil, diltiazem
Nifedipine
(a dihydropyridine)
Nonselective block of L-type
calcium channels in vessels and
heart
Block of vascular L-type calcium
channels>cardiac channels
Reduced vascular resistance, cardiac
rate, and cardiac force results in
decreased oxygen demand
Like verapamil and diltiazem; less
cardiac effect
Prophylaxis of angina,
hypertension
Prophylaxis of angina,
hypertension
Oral, IV, duration 4-8 h Toxicity:
atrioventricular block, acute heart
failure, constipation, edema
Interactions: Additive with other
cardiac depressants and hypotensive
drugs
Oral, duration 4-6 h Toxicity:
Excessive hypotension Interactions:
Additive with other vasodilators
MISCELLANEOUS
Ranolazine
Inhibits late sodium current in heart
also may modify fatty acid
oxidation
Reduces cardiac oxygen demand
fatty acid oxidation modification may
improve efficiency of cardiac oxygen
utilization
Prophylaxis of angina Oral, duration 6-8 h Toxicity: QT
interval prolongation, nausea,
constipation, dizziness Interactions:
inhibitors of CYP3A increase
ranolazine concentration and duration
of action
Which approach may not be used for variant angina?
A. Nitrates
B. Calcium Channel blockers
C. blockers
D. Angioplasty